Assessment of Peripheral and Tumor Specific Tregs and Th17 cells in Patients with Endometrial Cancer

Objective The frontline treatment for endometrial cancer (EC) is a hysterectomy; immunotherapy is approved, but has limited efficacy in all EC genotypes (mismatch repair genotypes). Understanding how EC pathogenesis affects the immune response is essential to determine effective interventions. Systemic inflammation, driven by T helper 17 (Th17) cells is induced in many cancers, while tumor induction of suppressive T regulatory cells (Tregs) is critical for immune evasion. We hypothesized that patients with EC have peripheral inflammation (evidenced by increased Th17:Treg ratio); yet, the EC tumor microenvironment (TME) remains immune tolerant (high Treg localization). Methods We collected peripheral blood and endometrial tissue from 61 patients with EC and 15 controls on the day-of-surgery, and blood post-surgical intervention (PSI). Peripheral Tregs and Th17 populations were examined via fluorescence activated cell sorting, plasma cytokine levels were measured utilizing immune assays, and tissue abundance of Th17 and Tregs via immunohistochemistry. Results Compared to controls, patients with early-stage (I, II) EC exhibited decreased peripheral unconventional Tregs (uTregs) and total Tregs, without changes in Th17 cell populations or the overall peripheral Th17:Treg ratio. Patients with proficient MMR genotyping also had reduced peripheral Treg populations. Patients with advanced disease (III, IV) had elevated peripheral inflammatory cytokines. The TME, regardless of stage, had increased abundance of Foxp3 + , but decreased RORγt + cells. EC patients had reduced peripheral inflammatory cytokine production at PSI. Conclusions EC patients exhibited increased peripheral inflammation, which decreased after tumor removal. EC TME indicated potential immune evasion through increased Tregs, but decreased Th17 localization within the tumor.